Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function

RATIONALE: Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood. OBJECTIVES: Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function. METHODS: Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV(1). SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus. MAIN RESULTS: Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p < 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV(1) (F+1, M+1, T1, and T2; p < or = 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18-4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma. CONCLUSIONS: Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.     

Sex Differences in Coronary Artery and Thoracic Aorta Calcification and Their Association With Cardiovascular Mortality in Heavy Smokers

ObjectivesThe aim of this study was to investigate sex differences in the prevalence, extent, and association of coronary artery calcium (CAC) and thoracic aorta calcium (TAC) scores with cardiovascular mortality in a population eligible for lung screening.BackgroundCAC and TAC scores derived from chest computed tomography (CT) might be useful biomarkers for individualized cardiovascular disease prevention and could be especially relevant in high-risk populations such as heavy smokers. Therefore, it is important to know the prevalence of arterial calcifications in male and female heavy smokers, and if there are differences in the predictive value calcifications carry.MethodsWe performed a nested case–control study with 5,718 participants of the CT arm of the NLST (National Lung Screening Trial). Prevalence and extent of CAC and TAC were resampled to the full cohort to provide unbiased estimates of the typical calcium burden of male and female heavy smokers. Weighted Cox proportional hazards regression was used to assess differences in the association of CAC and TAC scores with all-cause and cardiovascular mortality.ResultsCAC was substantially more common and more severe in men (prevalence: 81% vs. 60%; median volume: 104 mm³ vs. 12 mm³). Women had CAC comparable to that of men who were 10 years younger. TAC was equally common in men and women, with a tendency to be more pronounced in women (prevalence: 92% vs. 93%; median volume: 388 mm³ vs. 404 mm³). Both types of calcification were associated with increased cardiovascular and all-cause mortality. TAC scores improved the prediction of coronary heart disease mortality over CAC in men, but not in women. In both sexes, TAC, but not CAC, was associated with cardiovascular mortality other than coronary heart disease.ConclusionsCAC develops later in women, whereas TAC develops equally in both sexes. CAC is strongly associated with coronary heart disease, whereas TAC is especially associated with extracardiac vascular mortality in either sex.     

Safety is part of quality: a proposal for a continuum in performance measurement

Objectives Safer care is a strategic priority for health care organizations worldwide. Yet, the measurement and evaluation of key processes and outcomes associated with safer care remains challenging, even with existing performance measurement indicators. The multi‐national Quality Indicator Project (QI Project^®) data are analysed to [ 1 ] document the patterns of safety indicators used between 1999 and 2006 among hospitals in Asia, Europe and the USA; and [ 2 ] to identify trends in using both organization‐level and patient‐level data in hospital performance improvement. Design and setting Retrospective data are used to ascertain how the use of safety indicators has changed in comparison to other QI Project^® indicators. ‘Continent’ rather than ‘hospital’ is used as the unit of analysis and P‐values of the differences in use percentages across Asia, Europe and the USA are calculated. Results There was a significant increase in the use of QI Project^® indicators in Asia between 1999 and 2006. Measured as the mean percentage of usage, the safety versus ‘all other’ indicators' increase in Asia was 43.7% versus 27% (P < 0.05) and 37.2% versus 24.4% (P < 0.05), respectively, during the study's time period. The European participants used both safety and all other indicators less frequently, 14.7% versus 18% (P < 0.05) and 9.5% versus 19.8% (P < 0.05), respectively. Finally, USA hospitals demonstrated a larger difference in the decrease of QI Project^® indicator use than European hospitals between the ‘safety’ and ‘all other’ indicators, 12.7% decrease for safety indicators and 7.1% for all others (P < 0.05). These findings are consistent with trends reported in a previous study. Conclusion Traditional performance measures continue to assist hospitals in identifying crucial aspects of safety in the delivery of care. Building on the findings of a previous study, there are emerging trends in the type of measures used in hospitals in Asia, Europe and the USA pursuing the improvement of overall performance. The increasing use of patient‐level data specifically, in tandem with organizational level indicators, may signal the continuum of measurement strategies, now still predominately in the USA but anticipated to be adopted both in Europe and Asia.     

Autonomous surgical robotics using 3-D ultrasound guidance: feasibility study

The goal of this study was to test the feasibility of using a real-time 3D (RT3D) ultrasound scanner with a transthoracic matrix array transducer probe to guide an autonomous surgical robot. Employing a fiducial alignment mark on the transducer to orient the robot's frame of reference and using simple thresholding algorithms to segment the 3D images, we tested the accuracy of using the scanner to automatically direct a robot arm that touched two needle tips together within a water tank. RMS measurement error was 3.8% or 1.58 mm for an average path length of 41 mm. Using these same techniques, the autonomous robot also performed simulated needle biopsies of a cyst-like lesion in a tissue phantom. This feasibility study shows the potential for 3D ultrasound guidance of an autonomous surgical robot for simple interventional tasks, including lesion biopsy and foreign body removal.     

A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor

In Philadelphia-positive (Ph(+)) leukemia, point mutations within the Bcr-Abl kinase domain emerged as a major mechanism of resistance to imatinib mesylate. We established a cell-based screening strategy for detection of clinically relevant point mutations using Bcr-Abl-transformed Ba/F3 cells. We identified 32 different single-point mutations within the kinase domain of Bcr-Abl. The pattern and frequency of mutations in this cell culture-based screen resembled the pattern and frequency observed in resistant patients. We then applied this screen to an alternative Abl kinase inhibitor. Using PD166326, the frequency of resistant colonies emerging at 5 to 10 times the median growth inhibition (IC50) of PD166326 was significantly lower than with imatinib. In addition, PD166326 produced a distinct pattern of Bcr-Abl mutations. The majority of mutations that came up with both imatinib and PD166326 could effectively be suppressed by increasing the dose of PD166326 to 50 to 500 nM. In contrast, only a few mutations could be suppressed by increasing the imatinib dose to 5 to 10 microM. However, 3 mutations affecting F317 displayed complete resistance to PD166326, but could be effectively inhibited by standard concentrations of imatinib. Thus, this robust and simple screening system provides a rational basis for combinatorial and sequential treatment strategies in targeted cancer therapy.     

Airway obstruction in systolic heart failure – COPD or congestion?

Background

The diagnosis of chronic obstructive pulmonary disease (COPD) in patients with systolic heart failure (SHF) is challenging because symptoms of both conditions overlap. We aimed to estimate the prevalence, correlates and prognostic impact of true COPD in patients with SHF.

Methods

To diagnose COPD under stable conditions according to the guidelines, pulmonary function testing (PFT) was performed in 619 patients six months after hospitalization for congestive SHF. In 272 patients, PFT had been also performed prior to discharge.

Results

In the total cohort, COPD was reported in 23% (144/619). PFT under stable conditions revealed that COPD was absent in 73% (449/619), unconfirmed in 18% (112/619), and proven in 9% (58/619). In 272 patients with serial PFT, initial airway obstruction was found in 19% (51/272) but had resolved in 47% of those (24/51) after six months. Initial hyperinflation detected by bodyplethysmography strongly predicted proven COPD six months later: odds ratio for elevated intrathoracic gas volume 12.8, 95% confidence interval (CI) 2.5–65.9; p = 0.002.After a median follow-up of 34 months, 27% of the total cohort (165/619) had died. Only proven COPD was associated with an increased mortality risk after adjustment for age, sex, NYHA functional class, ejection fraction, atrial fibrillation, smoking, renal dysfunction and diabetes: hazard ratio 1.64, 95%CI 1.03–2.63; p = 0.039.

Conclusions

Airway obstruction is a dynamic phenomenon in SHF. Therefore, a valid diagnosis of COPD in SHF demands serial PFT under stable conditions with special attention to hyperinflation. COPD proven by PFT is associated with an increased all-cause mortality risk.     

COVID-19 in IBD: The experience of a single tertiary IBD center

BackgroundItaly has been one of the most affected countries in the world by COVID-19. There has been increasing concern regarding the impact of COVID‐19 on patients with inflammatory bowel disease (IBD), particularly in patients treated with immunosuppressants or biologics. The aim of our study is to understand the incidence of COVID-19 in a large cohort of patients with IBD. Furthermore, we analyzed possible risk factors for infection and severity of COVID-19.MethodsThis was an observational study evaluating the impact of COVID-19 on IBD patients in a single tertiary center. A 23 multiple-choice-question anonymous survey was administered to 1200 patients with IBD between March 10th and June 10th 2020.Results1158 questionnaires were analyzed. The majority of patients had Crohn's disease (CD) (60%) and most of them were in clinical remission. Among the 26 patients (2.2%) who tested positive for COVID-19, only 5 (3CD) were on biological treatment and none required hospitalization. Two patients died and were on treatment with mesalazine only. Of the 1158 patients, 521 were on biological therapy, which was discontinued in 85 (16.3%) and delayed in 195 patients (37.4%). A worsening of IBD symptoms was observed in 200 patients on biological therapy (38.4%). Most of these patients, 189 (94.5%), had stopped or delayed biological treatment, while 11 (5.5%) had continued their therapy regularly (p<0.001).ConclusionsOur data are in line with the current literature and confirm a higher incidence compared to the general population. Biological therapy for IBD seems to not be a risk factor for infection and should not be discontinued in order to avoid IBD relapse.     

Executive function in adolescents with ADHD

OBJECTIVE: The aim of this study was to clarify executive function weakness in attention-deficit/hyperactivity disorder (ADHD) during adolescence and determine the specificity of executive function weakness to ADHD symptom domains. METHOD: A total of 182 adolescents (105 boys), ages 13 to 17 years, completed a multistage diagnostic assessment; 85 were diagnosed with ADHD: 43 primarily Inattentive type (ADHD-PI) and 42 Combined type (ADHD-C). Participants completed the Stop, Trail Making, Wisconsin Card Sort, and Stroop tasks. RESULTS: The ADHD group exhibited impaired performance compared with the non-ADHD group on executive function measures (multivariate p < .05); there were no ADHD subtype differences. A composite executive function factor was significantly related to inattentive but not hyperactive-impulsive symptoms. CONCLUSIONS: Executive function weakness in adolescent ADHD is specifically related to symptoms of inattention-disorganization. Results are congruent with a dual-pathway model of ADHD cognitive mechanisms.     

Epithelioid hemangioendotheliomas of the liver and lung in children and adolescents

Epithelioid hemangioendothelioma (EHE) is a rare, vascular sarcoma. Visceral forms arise in the liver/ lungs. We review the clinical and molecular phenotype of pediatric visceral EHE based on the case of a 9‐year‐old male child with EHE of the liver/lungs. His tumor expressed the EHE‐specific fusion oncogene WWTR1‐CAMTA1. Molecular characterization revealed a low somatic mutation rate and activated interferon signaling, angiogenesis regulation, and blood vessel remodeling. After polychemotherapy and resection of lung tumors, residual disease remained stable on oral lenalidomide. Literature review identified another 24 children with EHE of the liver/lungs. Most presented with multifocal, systemic disease. Only those who underwent complete resection achieved complete remission. Four children experienced rapid progression and died. In six children, disease remained stable for years without therapy. Two patients died from progressive EHE 21 and 24 years after first diagnosis. Natural evolution of pediatric visceral EHE is variable, and long‐term prognosis remains unclear.